Administration of pyridinedicarboxylic acid compounds for stimulating or inducing the growth of human keratinous fibers and/or arresting their loss

ABSTRACT

The invention relates to the use in a composition for caring for human hair or eyelashes of an effective amount of a pyridinedicarboxylic acid derivative of general formula (I) or of one of its salts, 
     
       
         
         
             
             
         
       
     
     in which R 1  and R 2  represent, independently of one another, OH, OR′, —NH 2 , —NHR′ or —NR′R″, and R′ and R″ represent, independently of one another, a saturated or unsaturated and linear or branched C 1 -C 18  alkyl radical or an aryl radical, this alkyl or aryl radical optionally being substituted by at least one OH, alkoxy, acyloxy, amino or alkylamino group, or R′ and R″ together represent a heterocycle, the composition being intended to induce and/or stimulate the growth of human keratinous fibers, such as the hair and eyelashes, and/or slow down their loss; the invention also relates to a cosmetic treatment intended to stimulate the growth of human keratinous fibers, such as the hair and eyelashes, and/or slow down their loss.

CROSS-REFERENCE TO PRIORITY/PROVISIONAL APPLICATIONS

This application claims priority under 35 U.S.C. § 119 of FR-02/04527,filed Apr. 11, 2002, and of provisional application Ser. No. 60/372,414,filed Apr. 16, 2002, both hereby expressly incorporated by reference.This application is also a continuation of said '414 provisional.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

A subject-matter of the invention is the use of an effective amount of apyridinedicarboxylic acid derivative or of one of its salts in acomposition intended to induce and/or stimulate the growth of humankeratinous fibers and in particular of human hair and eyelashes and/orto slow down their loss. In addition, it relates to a cosmetic treatmentprocess intended to stimulate the growth of human keratinous fibers,such as the hair and eyelashes, and/or to retard their loss.

2. Description of the Prior Art

Hair growth and its replacement are mainly determined by the activity ofthe hair follicles and their matrix environment. Their activity iscyclical and comprises essentially three phases, namely the anagenicphase, the catagenic phase and the telogenic phase.

The anagenic phase (active or growth phase), which lasts several yearsand during which the hair grows longer, is followed by a very short andtransitory catagenic phase, which lasts a few weeks, and then by atelogenic phase or resting phase, which lasts a few months.

At the end of the resting period, the hair falls out and another cyclerecommences. The head of hair is thus constantly replaced and, of theapproximately 150,000 hairs which a head of hair comprises,approximately 10% are at rest and will be replaced in the months tocome.

Natural hair loss can be estimated, on average, at a few hundredindividual hairs per day for a normal physiological state. This processof constant physical replacement undergoes a natural change with aging,the hair becomes finer and its cycles shorter.

In addition, various causes can result in significant hair loss, whethertemporary or definitive. Hair loss, in particular alopecia, isessentially due to disturbances in hair replacement. These disturbancesresult first in the acceleration in the frequency of the cycles, at theexpense of the quality of the hair and then of their quantity. The bulbsgradually become smaller and, at the same time, the latter becomeisolated by gradual thickening of the perifollicular collagen matrix andof the external connective tissue sheath. Revascularization about thehair follicle is therefore rendered more difficult cycle after cycle.Individual hairs regress, becoming smaller until no more than anunpigmented down, and this phenomenon results in a gradual thinning ofthe head of hair.

Areas are preferentially affected, in particular the temporal or frontalregions in men and, in women, diffuse alopecia of the vertex isobserved.

The term “alopecia” also covers a whole family of conditions of the hairfollicle having, as final consequence, the definitive loss, partial orgeneral, of the hair. It relates more particularly to androgenicalopecia. In a large number of cases, early hair loss occurs ingenetically predisposed individuals. This is then androchronogeneticalopecia; this form of alopecia concerns men in particular.

Furthermore, it is known that certain factors, such as a hormoneimbalance, a physiological stress or malnutrition, can accentuate thephenomenon. In addition, hair loss or detrimental change can be relatedto seasonal phenomena.

Generally, any factor which influences these processes, namely theacceleration in the frequency of the cycles, the gradual reduction insize of the bulbs, the gradual thickening of the perifollicular collagenmatrix, the thickening of the external connective tissue sheath and thereduction in vascularization, will have an effect on the growth of thehair follicles.

SUMMARY OF THE INVENTION

It has now unexpectedly been found that pyridinedicarboxylic acids andcertain derivatives of these pyridinedicarboxylic acids, in particularesters and amides, surprisingly possess a favorable activity inmaintaining and/or improving the density of human keratinous fibers andin particular the hair density in man and/or reducing the variation inthe diameters of keratinous fibers and more especially of head hairs inman. Increasing the density of keratinous fibers, in particular hairfibers, is understood to mean increasing the number of keratinousfibers, in particular of head hairs, per cm² of skin and in particularof scalp.

The present invention therefore features the use of at least onepyridinedicarboxylic acid derivative of general formula (I) or of one ofits salts

in which R₁ and R₂ represent, independently of one another, OH, OR′,—NH₂, —NHR′ or —NR′R″, and R′ and R″ represent, independently of oneanother, a saturated or unsaturated and linear or branched C₁-C₁₈ alkylradical or an aryl radical, this alkyl or aryl radical optionally beingsubstituted by at least one OH, alkoxy, acyloxy, amino or alkylaminogroup, or R′ and R″ together represent a heterocycle, in a cosmeticcomposition for caring for and/or making up keratinous fibers or for thepreparation of a composition for caring for and/or treating keratinousfibers, to or intended to induce and/or stimulate the growth of humankeratinous fibers and/or slow down their loss and/or increase theirdensity.

This invention also features a cosmetic regime or regimen comprisingadministering at least one pyridinedicarboxylic acid derivative offormula (I) or one of its salts as defined above in a cosmeticcomposition as agent for inducing and/or stimulating the growth of humankeratinous fibers and/or slowing down their loss and/or increasing theirdensity.

The human keratinous fibers to which the invention applies are inparticular the hair, eyebrows, eyelashes, beard hairs, moustache hairsand pubic hairs. More particularly, the invention applies to human hairand/or eyelashes.

Consequently, the invention also relates to the cosmetic use of at leastone pyridinedicarboxylic acid derivative of formula (I) or of one of itssalts in a cosmetic composition for human hair care, for treatingandrogenic alopecia, and to the use of at least one pyridinedicarboxylicacid derivative of formula (I) or of one of its salts for thepreparation of a composition for human hair care intended to treatandrogenic alopecia. Thus, this composition makes it possible to keepthe head of hair in good condition and/or to combat natural hair loss inmen.

A further subject-matter of the invention is the cosmetic use of atleast one pyridinedicarboxylic acid derivative of formula (I) or of oneof its salts as defined above in a cosmetic composition for caring forand/or making up human eyelashes or for the preparation of a compositionfor caring for and/or treating human eyelashes, to or intended to induceand/or stimulate the growth of the eyelashes and/or increase theirdensity. This composition thus makes it possible to keep the eyelashesin good condition and/or to improve their condition and/or theirappearance.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

According to the invention, “at least one” derivative means one or more(2, 3 or more) derivatives.

The derivatives to which the invention applies are known as such; theycan be manufactured in a known way.

Thus, pyridine-2,4-dicarboxylic and pyridine-2,5-dicarboxylic acids havebeen described as very weak inhibitors of proline hydroxylase (K.Majamaa et al., Eur. J. Biochem., 138, 1984, 239-245). Sharir et al.have suggested the use of pyridine-2,4-dicarboxylic acid to slow downthe healing of a surgical wound (Current Eye Research, vol. 12(6), 1993,15 553-559).

U.S. Pat. No. 4,717,727 teaches that esters of pyridine-2,4-dicarboxylicand pyridine-2,5-dicarboxylic acids can be used in the treatment ofpathologies related to collagen metabolism, on the one hand, and asimmunosuppressant, on the other hand.

To the knowledge of the assignee hereof, the prior art does not teach orsuggest that the pyridinedicarboxylic acid derivatives or one of theirsalts targeted by the present invention have the property of inducingand/or stimulating the growth of human keratinous fibers and inparticular of human hair and of the eyelashes and/or of slowing downtheir loss and/or of increasing their density.

The C₁-C₁₈ alkyl radical is preferably a saturated or unsaturated alkylcomprising from 1 to 10 carbon atoms, such as methyl, ethyl, tert-butyl,isopropyl, hexyl and others. The alkyl can comprise at least onecarbon-carbon double bond or one carbon-carbon triple bond, such as, forexample, —CH═CH₂, —CH₂—CH═CH—CH₃ or —CH₂—C≡CH.

According to the present invention, the term “alkoxy” is understood tomean an —O—R group in which R is a C₁-C₁₈ alkyl group as defined above.The term “acyloxy” is understood to mean an —O—CO—R group in which R isa C₁-C₁₈ alkyl group as defined above. The term “alkylamino” isunderstood to mean an —NH—R group in which R is a C₁-C₁₈ alkyl group asdefined above.

The aryl radical can represent the phenyl or naphthyl radical.

When R′ and R″ together represent the heterocycle, they can represent aring with 4 to 7 atoms and better still with 5 to 6 atoms, comprisingfrom 1 to 4 heteroatoms chosen from O, S or N, it being possible forthis ring to be saturated or unsaturated. Mention may be made, asheterocycle, of the piperidine, morpholine, imidazole, pyrazole,piperazine, pyrrolidine or thiazolidine rings.

In particular, R′ and R″ represent a C₁-C₁₈ and better still C₁-C₁₀alkyl radical optionally substituted by an alkoxy or acyloxy group.

R₁ and R₂ preferably represent, independently of one another,

COR₁ and COR₂ are preferably respectively in the 2 and 3 or 2 and 4positions of the pyridine ring. However, they can be respectively in the2 and 5 positions.

According to a preferred embodiment of the invention, the followingpyridinedicarboxylic acid derivatives are used:

-   pyridine-2,4-dicarboxylic acid or its zinc or sodium salt,-   pyridine-2,3-dicarboxylic acid or its zinc or sodium salt,-   dimethylpyridine-2,4-dicarboxylate,-   dimethylpyridine-2,3-dicarboxylate,-   diethyl pyridine-2,4-dicarboxylate,-   diethyl pyridine-2,3-dicarboxylate,-   diethyl pyridine-2,5-dicarboxylate,-   dimethylpyridine-2,5-dicarboxylate,-   diisopropyl pyridine-2,4-dicarboxylate,-   2,4-di(n-propylamido) pyridine, (derivative of formula (I) with    R₁=R₂═NH—(CH₂)₂—CH₃),-   di(acetyloxymethyl)pyridine-2,4-dicarboxylate (derivative of    formula (I) such that R₁ and R₂ represent O—CH₂—O—COCH₃),-   2,4-di(2-hydroxyethylamido)pyridine,-   2,4-di(3-hydroxypropylamido)pyridine.

Use is advantageously made of esters of pyridinedicarboxylic acid, asthey have a better cutaneous penetration, and in particular diethylpyridine-2,4-dicarboxylate.

Salts of compounds of formula (I) is understood to mean, according tothe invention, the organic or inorganic salts of a compound of formula(I), said salts being physiologically acceptable.

Mention may be made, as inorganic salts which may be used according tothe invention, of double sodium or potassium salts and zinc (Zn²⁺),calcium (Ca²⁺), copper (Cu²⁺), iron (Fe²⁺), strontium (Sr²⁺), magnesium(Mg²⁺) or manganese (Mn²⁺) salts; hydroxides, carbonates or chlorides.

The organic salts which can be used according to the invention are, forexample, triethanolamine, monoethanolamine, diethanolamine,hexadecylamine, N,N,N′,N′-tetrakis(2-hydroxypropyl)ethylenediamine ortris(hydroxymethyl)aminomethane salts.

It is thus understood that, in the text, unless otherwise indicated, theuse of the term compound of formula (I) should be understood as meaningthe compound of formula (I) in the salified or nonsalified form.

The effective amount of a compound of formula (I) or of one of its saltscorresponds, of course, to the amount necessary to produce the desiredresult (namely, to increase the density of keratinous fibers and inparticular the head hairs or to promote their growth). A person skilledin the art is therefore in a position to evaluate this effective amount,which depends on the nature of the compound used and on the person towhich it is applied.

To give an order of magnitude, according to the invention, the compoundof formula (I) or one of its salts can be used in an amount representingfrom 10⁻³% to 10% of the total weight of the composition and preferablyin an amount representing from 10⁻²% to 5% of the total weight of thecomposition, for example from 0.5% to 2%.

Also, the composition must comprise a nontoxic physiologicallyacceptable medium capable of being applied to the skin, including thescalp and eyelids, or to the keratinous fibers of human beings. The term“cosmetic” is understood to mean, within the meaning of the invention, acomposition with a pleasant appearance, pleasant smell and pleasantfeel.

The composition according to the invention can be for cosmetic orpharmaceutical use. Preferably, the composition according to theinvention is for cosmetic use. The compound of formula (I) or one of itssalts can be used in a composition which has to be ingested, injected orapplied to the skin or keratinous fibers (over any cutaneous area of thebody and fibers to be treated).

According to the invention, the compound of formula (I) or one of itssalts can be used via the oral route in an amount of 0.1 to 300 mg perday, for example of 5 to 10 mg/d.

A preferred composition of the invention is a composition for cosmeticuse for topical application to the skin and keratinous fibers and moreparticularly to the scalp, hair and eyelashes.

Depending on the method of application, this composition can be providedin any pharmaceutical dosage form normally used in the cosmetic andpharmaceutical fields.

For topical application to the skin, including the scalp, thecomposition can have the form in particular of an aqueous, alcoholic oraqueous/alcoholic solution or suspension, of an oily suspension orsolution, of an emulsion or dispersion with a liquid or semi-liquidconsistency obtained by dispersion of a fatty phase in an aqueous phase(O/W) or vice versa (W/O), of a dispersion or emulsion with a softconsistency, of an aqueous or aqueous/alcoholic or oily (anhydrous) gel,of a free or compact powder to be used as is or to be incorporated in aphysiologically acceptable medium (excipient), or also of microcapsulesor microparticles, or of vesicular dispersions of ionic and/or nonionictype.

It is also possible to envisage a composition in the form of a foam oralternatively in the form of an aerosol composition also comprising apressurized propellant.

In particular, the composition for application to the scalp or hair canbe provided in the form of a hair care lotion, for example for daily ortwice-weekly application, of a shampoo or of a hair conditioner, inparticular for twice-weekly or weekly application, of a liquid or solidsoap for cleaning the scalp for daily application, of a product forshaping the hairstyle (lacquer, hairsetting product, styling gel), of atreatment mask, of a cream or of a foaming gel for cleaning the hair. Itcan also be provided in the form of a hair dye or mascara to be appliedwith a brush or comb.

Furthermore, for application to the eyelashes or hairs, the compositionto which the invention applies can be provided in the form of apigmented or nonpigmented mascara, to be applied with a brush to theeyelashes or alternatively to the beard or moustache hairs.

For use by injection, the composition can be provided in the form of anaqueous lotion or of an oily suspension, for example in the serum form.For use by ingestion or the oral route, it can be provided in the formof capsules, of granules, of syrups to be taken orally or of tablets.

According to a specific embodiment, the composition to which theinvention applies is provided in the form of a hair cream or lotion, ofa shampoo, of a hair conditioner, of a hair mascara or of a mascara forthe eyelashes.

The amounts of the various constituents of the composition according tothe invention are those conventionally used in the fields underconsideration. In addition, this composition is prepared according toconventional methods. It can thus be provided in the form of a lotion,serum, milk, O/W or W/O cream, gel, ointment, pomade, powder, balm,patch, impregnated pad, soap, bar or foam.

When the composition is an emulsion, the proportion of the fatty phasecan range from 2% to 80% by weight and preferably from 5% to 50% byweight with respect to the total weight of the composition.

The aqueous phase is adjusted according to the content of fatty phaseand of compound(s) (I) and according to the content of possibleadditional ingredients, in order to obtain 100% by weight. In practice,the aqueous phase represents from 5% to 99.9% by weight.

The fatty phase can comprise fatty or oily compounds which are liquid atambient temperature (25° C.) and atmospheric pressure (760 mmHg),generally known as oils. These oils may or may not be compatible withone another and may form a macroscopically homogeneous liquid fattyphase or a two- or three-phase system.

The fatty phase can, in addition to the oils, comprise waxes, gums,lipophilic polymers, or “pasty” or viscous products comprising solidparts and liquid parts.

The aqueous phase comprises water and optionally an ingredient misciblein any proportion with water, such as lower C₁ to C₈ alcohols, forexample ethanol or isopropanol, polyols, such as propylene glycol,glycerol or sorbitol, or else acetone or ether.

The emulsifiers and coemulsifiers used in the composition in the form ofan emulsion are chosen from those conventionally used in the cosmetic orpharmaceutical field. The emulsifier and the co-emulsifier are presentin the composition in a proportion ranging from 0.1% to 30% by weightand preferably from 0.5% to 20% by weight with respect to the totalweight of the composition and better still from 1% to 8%. In addition,their nature depends on the sense of the emulsion. In addition, theemulsion can comprise lipid vesicles and in particular liposomes.

When the composition is an oily solution or gel, the fatty phase canrepresent more than 90% of the total weight of the composition.

Advantageously, for a hair application, the composition is an aqueous,alcoholic or aqueous/alcoholic solution or suspension and better still awater/ethanol solution or suspension. The alcohol fraction can representfrom 5% to 99.9% and better still from 8% to 80%.

For a mascara application, the composition is a wax-in-water orwax-in-oil dispersion, a gelled oil or an aqueous gel, with or withoutpigment.

The composition to which the invention applies can also compriseadjuvants usual in the cosmetic or pharmaceutical field chosen fromhydrophilic or lipophilic gelling agents or thickeners, hydrophilic orlipophilic additives, preservatives, antioxidants (carotenoids),solvents, fragrances, fillers, odor absorbers, electrolytes,neutralizing agents, UV blocking agents, such as sunscreens,film-forming polymers, cosmetic and pharmaceutical active principleswith a beneficial effect on the skin or keratinous fibers (such asvitamins) and coloring materials, which may or may not be soluble in themedium. The amounts of these various adjuvants are those conventionallyused in the cosmetic field, for example from 0.01% to 20% and betterstill from 0.1% to 10% of the total weight of the composition. Theseadjuvants, depending on their nature, can be introduced into the fattyphase, into the aqueous phase and/or into the lipid vesicles and inparticular liposomes.

Mention may be made, as oils or waxes which can be used in theinvention, of mineral oils (liquid petrolatum, hydrogenatedisoparaffin), vegetable oils (liquid fraction of karite butter,sunflower oil, soybean oil, wheat germ oil), animal oils(perhydrosqualene), synthetic oils (purcellin oil, fatty acid esters),silicone oils or waxes (linear or cyclic polydimethylsiloxanes,cyclomethicone, phenyl trimethicone), fluorinated oils(perfluoropolyethers), beeswax, candelilla wax, rice wax, carnauba wax,paraffin wax or polyethylene wax. Fatty alcohols and fatty acids(stearic acid, linoleic acid, linolenic acid) can be added to these oilsand waxes.

Mention may be made, as emulsifiers which can be used in the invention,of, for example, glyceryl stearate or laurate, polyoxyethylenatedsorbitol stearate or oleate (for example, polysorbate 60 and thePEG-6/PEG-32/glycol stearate mixture sold under the name of Tefose® 63by Gattefosse) or (alkyl) dimethicone copolyols.

Mention may be made, as solvents which can be used in the invention, oflower alcohols, in particular ethanol and isopropanol, propylene glycolor certain light cosmetic oils.

Mention may be made, as hydrophilic gelling agents which can be used inthe invention, of carboxy-vinyl polymers (carbomer), acrylic copolymers,such as acrylate/alkyl acrylate copolymers, polyacrylamides,polysaccharides, such as hydroxypropylcellulose, clays and natural gumsand mention may be made, as lipophilic gelling agents, of modifiedclays, such as bentones, metal salts of fatty acids, such as aluminumstearates, hydrophobic treated silica, ethylcellulose and theirmixtures.

The composition can comprise other active principles than those offormula (I) which can be hydrophilic, such as proteins or proteinhydrolysates, amino acids, polyols, urea, allantoin, sugars and sugarderivatives, water-soluble vitamins, or plant extracts (of Iridaceae orof soya), it then being possible for these extracts to comprise or notto comprise isoflavones; or lipophilic, such as retinol (vitamin A) andits derivatives, in particular ester (palmitate), tocopherol (vitamin E)and its derivatives, in particular ester (acetate, palmitate), essentialfatty acids, such as eicosatetraenoic acid and eicosatrienoic acid ortheir esters and amides, ceramides, essential oils, esters of hydroxyacids, or phospholipids, such as lecithin; or soluble in alcoholicsolvents, such as lactones (kawain); or their mixtures.

According to the invention, it is possible, inter alia, to combine thecompound of formula (I) or one of its salts with other additional activecompounds promoting in particular the regrowth of human keratinousfibers and/or limiting their loss. These additional compounds are chosenin particular from:

hormones, in particular of plant origin, for example estriol or itsanalogues, thyroxine and its salts, or progesterone;

antibacterial agents, such as macrolides, pyranosides and tetracyclinesand in particular erythromycin;

calcium antagonist agents, such as cinnarizine, diltiazem, nimodipine,verapamil and nifedipine;

microorganism extracts, in particular bacterial extracts;

agents which modulate cutaneous differentiation and/or proliferation,such as retinoic acid and its isomers, retinol and its esters, vitamin Dand its derivatives, or oestrogens, such as oestradiol;

agents which modulate bacterial adhesion to the skin and/or mucousmembranes, such as honey, in particular acacia honey, and certain sugarderivatives;

agents for combating parasites, in particular metronidazole, crotamitonor pyrethroids;

antifungals, in particular compounds belonging to the imidazole class,such as econazole, ketoconazole or miconazole or their salts, nicotinicacid esters, including in particular tocopherol nicotinate, benzylnicotinate and C₁-C₆ alkyl nicotinates, such as methyl nicotinate orhexyl nicotinate; polyene compounds, such as amphotericin B, compoundsof the allylamine family, such as terbinafine, or alternativelyoctopirox, selenium derivatives or anthralin;

antiviral agents, such as acyclovir;

steroidal anti-inflammatory agents, such as cortico-steroids, forexample hydrocortisone, betamethasone valerate or clobetasol propionate,or nonsteroidal anti-inflammatory agents, such as ibuprofen and itssalts, diclofenac and its salts, acetylsalicylic acid, acetaminophen,glycyrrhetinic acid or α-bisabolol;

anaesthetic agents, such as lidocaine hydrochloride and its derivatives;

antipruriginous agents, such as thenaldine, trimeprazine orcyproheptadine;

keratolytic agents, such as α- and β-hydroxy-carboxylic orβ-ketocarboxylic acids, their salts, amides or esters, the lactones andtheir corresponding salts, and more particularly hydroxy acids, such asglycolic acid, lactic acid, salicylic acid, citric acid and generallyfruit acids, or salicylic acid derivatives, such as those carrying analkanoyl radical having from 2 to 12 carbon atoms in the 5 position ofthe benzene ring, such as 5-(n-octanoyl)salicylic acid;

agents for combating free radicals, such as α-tocopherol or its esters,superoxide dismutases, certain metal chelating agents or ascorbic acidand its esters;

antiseborrheics, such as progesterone;

antidandruff agents, such as octopirox or zinc pyrithione;

anti-acne agents, such as retinoic acid or benzoyl peroxide;

vasodilators, such as pyrimidine derivatives, for example2,4-diamino-6-piperidinopyrimidine 3-oxide or “minoxidil”, disclosed inU.S. Pat. Nos. 4,139,619 and 4,596,812, or diazoxide;

agents which reduce hair loss, such as aminexil or6-O-[(9Z,12Z)-octadeca-9,12-dienoyl]hexapyranose;

anti-androgen agents, such as oxendolone, spironolactone,diethylstilbestrol and flutamide;

steroidal or nonsteroidal inhibitors of 5α-reductases, such asfinasteride;

potassium channel agonists, such as cromakalim and nicorandil;

FP receptor (receptor to prostaglandins of type F) agonists, such aslatanoprost, bimatoprost, travoprost or unoprostone;

their mixtures.

The composition according to the invention can additionally comprisesubstances such as substance P, CGRP or bradykinin agonists orNO-synthase inhibitors, compounds described as being active in thetreatment of sensitive skin and as exhibiting anti-irritant effects, inparticular with respect to irritant compounds possibly present in thecompositions.

The composition according to the invention advantageously comprises atleast one additional active principle which promotes the regrowth ofhuman keratinous fibers and/or which limits the loss chosen fromaminexil, FP receptor agonists and vasodilators and more particularlychosen from aminexil, minoxidil, latanoprost and travoprost.

It is also possible to envisage that the composition comprising at leastthe compound of formula (I) or one of its salts is in the liposomedform, such as disclosed in particular in WO 94/22468, filed on 13 Oct.1994 by Anti Cancer, Inc. Thus, the compound encapsulated in theliposomes can be selectively delivered in the hair follicle.

The composition according to the invention, in particular the cosmeticcomposition, can be applied to the alopecic areas of the scalp and hairof an individual, and optionally left in contact for several hours andoptionally rinsed out.

It is possible, for example, to apply the composition comprising aneffective amount of a compound of formula (I) or of one of its salts inthe evening, to keep the latter in contact overnight and optionally toshampoo in the morning. These applications can be repeated daily for oneor more months, according to the individuals.

Thus, another subject-matter of the present invention is a process forthe cosmetic treatment of human keratinous fibers and/or of the skinwhence the said fibers emerge, including the scalp, characterized inthat it consists in applying, to the keratinous fibers and/or the skinwhence the said fibers emerge, a cosmetic composition comprising atleast one derivative of formula (I) or one of its salts, in leaving thelatter in contact with the keratinous fibers and/or the skin whence thesaid fibers emerge and optionally in rinsing the fibers and/or the skin.

This treatment process indeed exhibits the characteristics of a cosmeticprocess in so far as it makes it possible to improve the attractivenessof human keratinous fibers by giving them greater vigor and improvedappearance. In addition, it can be used daily for several months,without medical prescription.

More particularly, a subject-matter of the present invention is aprocess for the cosmetic care of human hair and/or the human scalp, forthe purpose of improving their condition and/or their appearance,characterized in that it consists in applying, to the hair and/or thescalp, a cosmetic composition comprising at least one derivative offormula (I) or one of its salts, in leaving the latter in contact withthe hair and/or the scalp and optionally in rinsing the hair and/or thescalp.

A further subject-matter of the invention is a process for the cosmeticcare of and/or for making up human eyelashes, for the purposes ofimproving their condition and/or their appearance, characterized in thatit consists in applying a mascara composition comprising at least onecompound of formula (I) or one of its salts and in leaving thiscomposition in contact with the eyelashes. This mascara composition canbe applied alone or as a base coat of a conventional pigmented mascaraand can be removed like a conventional pigmented mascara.

A further subject-matter of the invention is a composition for caringfor or making up keratinous fibers comprising, in a physiologicallyacceptable medium, in particular a cosmetic medium, at least onederivative of formula (I) or one of its salts as defined above and atleast one additional active principle which promotes the regrowth ofhuman keratinous fibers and/or which limits the loss chosen fromaminexil, FP receptor agonists and vasodilators and chosen moreparticularly from aminexil, minoxidil, latanoprost and travoprost.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative.

Example 1

Hair lotion: Diethyl pyridine-2,4-dicarboxylate 0.80 g Propylene glycol10.00 g Isopropyl alcohol q.s. for 100.00 g

1 ml of this lotion is applied to the scalp at a rate of once to twicedaily, the scalp being gently massaged for penetration of the activeprinciple into the epidermis. The head of hair is subsequently dried inthe open air. This lotion decreases hair loss and improves theappearance and the condition of the hair.

Example 2

Hair lotion: Diethyl pyridine-2,4-dicarboxylate 2 g Propylene glycol30.00 g Ethyl alcohol 40.00 g Water q.s. for 100.00 g

This lotion is applied to the scalp once to twice daily in a proportionof 1 ml per application, the scalp being gently massaged. The head ofhair is subsequently dried in the open air.

Example 3

Hair lotion: Diethyl pyridine-2,4-dicarboxylate 2 g Ethyl alcohol 40.00g Water q.s. for 100.00 g

This lotion is applied to the scalp once to twice daily in a proportionof 1 ml per application, the scalp being gently massaged. The hair issubsequently dried in the open air or using a hair dryer.

Example 4

Hair lotion: Diisopropyl pyridine-2,4-dicarboxylate 2 g Propylene glycol30.00 g Ethyl alcohol 40.00 g Water q.s. for 100.00 g

1 ml of this lotion is applied to the scalp at the rate of once to twicedaily, the scalp being gently massaged. The hair is subsequently driedin the open air or using a hair dryer.

Example 5

Thickened hair lotion: Dimethyl pyridine-2,4-dicarboxylate 0.50 g Kawain2.00 g Klucel G ®* 3.50 g Ethyl alcohol q.s. for 100.00 g

This thickened lotion is applied to the scalp once to twice daily in aproportion of 1 ml per application, the scalp being gently massaged. Thehair is subsequently dried in the open air or using a hair dryer.

Example 6

Hair lotion: Dimethyl pyridine-2,4-dicarboxylate 1.00 g Dowanol PM ®**20.00 g Klucel G ®* 3.00 g Ethyl alcohol 40.00 g Water q.s. for 100.00 g

This thickened lotion is applied to the scalp once to twice daily in aproportion of 1 ml per application, the scalp being gently massaged. Thehair is subsequently dried in the open air or using a hair dryer.

Example 7

Hair lotion: Sodium salt of pyridine-2,4-dicarboxylic acid 5.00 g Ethylalcohol 20.00 g Water q.s. for 100.00 g

This lotion is applied to the scalp once to twice daily in a proportionof 1 ml per application.

Example 8

Hair lotion: Diethyl pyridine-2,4-dicarboxylate 2 g Ethyl alcohol 50.00g Aminexil 1.50 g Water q.s. for 100.00 g

This lotion is applied to the scalp once to twice daily in a proportionof 1 ml per application, the scalp being gently massaged. The hair issubsequently dried in the open air or using a hair dryer.

Example 9

Hair lotion: Diethyl pyridine-2,4-dicarboxylate 2 g Aminexil 1.5 gPropylene glycol 30.00 g Ethyl alcohol 40.00 g Water q.s. for 100.00 g

This lotion is applied to the scalp once to twice daily in a proportionof 1 ml per application, the scalp being gently massaged. The head ofhair is subsequently dried in the open air.

Example 10

Composition for the oral route: Soft capsules having the followingcomposition are prepared in a way conventional to a person skilled inthe art: Hydrogenated soybean oil 40 mg Wheat germ oil 95 mg Soybeanlecithin 20 mg Natural tocopherols  5 mg Ascorbic acid 30 mg Dimethylpyridine-2,4-dicarboxylate 10 mg This composition is used once to twicedaily in a proportion of one capsule per absorption. *:Hydroxypropylcellulose, sold by Hercules **: Propylene glycol monomethylether, sold by Dow Chemical.

Example 11

Hair lotion: Na salt of pyridine-2,4-dicarboxylic acid 2 g Aminexil 1.5g Ethyl alcohol 40 g Water q.s. for 100.00 g

This lotion is applied to the scalp once to twice daily in a proportionof 1 ml per application, the scalp being gently massaged. The head ofhair is subsequently dried in the open air.

Example 12

Hair lotion: Diethyl pyridine-2,4-dicarboxylate 2 g Latanoprost 0.005 gPropylene glycol 30 g Ethyl alcohol 40 g Water q.s. for 100.00 g

This lotion is applied to the scalp once to twice daily in a proportionof 1 ml per application, the scalp being gently massaged. The head ofhair is subsequently dried in the open air.

Example 13 In Vivo Activity 1st Study:

Pyridine-2,4-dicarboxylic acid was tested in vivo on 25 men exhibitingandrogenetic alopecia of stage III to V according to the Hamiltonclassification.

It was studied at a concentration of 2%, formulated in a ternary lotionbased on propylene glycol, ethanol and water.

Each volunteer was treated once daily, 5 days per week, for 3 months, anarea of the scalp receiving 30 μl of the lotion comprising the activeprinciple and another area receiving the vehicle alone (placebo).

The evaluation of the effectiveness of the treatments was carried out bydetermining the total pilar density of hairs per cm² (DE) using thephototrichogram technique. This examination was carried out beforetreatment (M0) and after 3 months of treatment (M3).

The results (mean±standard deviation) and the variations with respect toM0 are presented in the following table:

2% Pyridine-2,4-dicarboxylic Placebo acid No. of No. of hairs/per cm² DEvariation hairs/per cm² DE variation (DE) (%) (DE) (%) M0 217 ± 50 / 213± 45 / M3 218 ± 57 0% 224 ± 53 4.4%

The results show an increase in the total density for the areas treatedwith pyridine-2,4-di-carboxylic acid, whereas those areas which havereceived the placebo do not change.

2nd Study:

Pyridine-2,4-dicarboxylic acid was tested in the form of the Na doublesalt formulated at a concentration of 5% in an aqueous/alcoholic lotion.

The study was carried out versus placebo on 22 men exhibitingandrogenetic alopecia of stage III to V according to the Hamiltonclassification.

Each volunteer was treated once daily, 5 days per week, for 3 months, anarea of the scalp receiving 30 μl of the lotion comprising the activeprinciple and another area receiving the vehicle alone.

The evaluation of the effectiveness of the treatments was carried out bydetermining the total pilar density of hairs per cm² (DE) using thephototrichogram technique. This examination was carried out beforetreatment (M0) and after 3 months of treatment (M3).

The results (mean±standard deviation) and the mean of the variation withrespect to M0 are presented in the following table:

5% Na disalt of Pyridine-2,4- Placebo dicarboxylic acid No. of No. ofhairs/per cm² DE variation hairs/per cm² DE variation (DE) (%) (DE) (%)M0 247 ± 52 / 249 ± 50 / M3 236 ± 52 −4.6% 246 ± 50 −0.97%

The results show a decrease in the total density over the areas whichhave received the placebo. This hair loss is 4 times smaller for theareas which have received the Na double salt ofpyridine-2,4-di-carboxylic acid.

The two studies, carried out in vivo on alopecic individuals, show anactivity of pyridine-2,4-dicarboxylic acid and of its Na double salt, incomparison with a placebo, in favor of an increase in or a maintenanceof the density of the hairs.

Each patent, patent application and literature article/report cited orindicated herein is hereby expressly incorporated by reference.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

1.-24. (canceled)
 25. A regime or regimen for inducing/stimulating thegrowth of human keratinous fibers and/or retarding the loss and/orincreasing the density thereof, comprising administering to anindividual subject in need of such treatment, a thus effective amount ofat least one compound having the following structural formula (I), orsalt selected from the group consisting of the double salt of sodium orof potassium, zinc (Zn²⁺), calcium (Ca²⁺), copper (Cu²⁺), iron (Fe²⁺),strontium (Sr²⁺), magnesium (Mg²⁺) and manganese (Mn²⁺) salts,triethanolamine, monoethanolamine, diethanolamine, hexadecylamine,N,N,N′,N′-tetrakis(2-hydroxypropyl)-ethylenediamine ortris(hydroxymethyl)aminomethane salts, hydroxides, carbonates andchlorides:

in which: R₁ and R₂, which may be identical or different, are each OH,OR′, wherein R′ represents a saturated or unsaturated linear or branchedC₁-C₁₈ alkyl radical.
 26. The regime or regimen as defined by claim 25,for inducing/stimulating the growth of human head hair, eyebrows,eyelashes, beard hairs, moustache hairs or pubic hairs and/or retardingthe loss and/or increasing the density thereof.
 27. A regime or regimenfor inducing/stimulating the growth of human head hair and/or retardingthe loss and/or increasing the density thereof, comprising topicallyapplying onto the hair and/or scalp of an individual in need of suchtreatment, a thus effective amount of at least one compound having thefollowing structural formula (I), or salt thereof:

in which: R₁ and R₂, which may be identical or different, are each OH,OR′, wherein R′ represents a saturated or unsaturated linear or branchedC₁-C₁₈ alkyl radical.
 28. A regime or regimen for treating androgenicalopecia, comprising administering to an individual in need of suchtreatment, a thus effective amount of at least one compound having thefollowing structural formula (I), or salt thereof:

in which: R₁ and R₂, which may be identical or different, are each OH,OR′, wherein R′ represents a saturated or unsaturated linear or branchedC₁-C₁₈ alkyl radical.
 29. The regime or regimen as defined by claim 25,wherein formula (I), R₁ and R₂, which may be identical or different, areeach:


30. The regime or regimen as defined by claim 25, wherein formula (I),R₁ and R₂, are respectively in the 2 and 3 or 2 and 4 positions of thepyridine ring.
 31. The regime or regimen as defined by claim 25,comprising administering a salt of said at least one compound of formula(I), selected from the group consisting of the double salt of sodium orof potassium, calcium (Ca²⁺), copper (Cu²⁺), iron (Fe²⁺), strontium(Sr²⁺), magnesium (Mg²⁺) and manganese (Mn²⁺) salts, triethanolamine,monoethanolamine, diethanolamine, hexadecylamine,N,N,N′,N′-tetrakis(2-hydroxypropyl)-ethylenediamine ortris(hydroxymethyl)aminomethane salts, hydroxides, carbonates andchlorides.
 32. The regime or regimen as defined by claim 25, comprisingadministering a thus effective amount of: pyridine-2,4-dicarboxylic acidor its sodium salt, pyridine-2,3-dicarboxylic acid or its sodium salt,dimethylpyridine-2,4-dicarboxylate, dimethylpyridine-2,3-dicarboxylate,diethyl pyridine-2,4-dicarboxylate, diethyl pyridine-2,3-dicarboxylate,diisopropyl pyridine-2,4-dicarboxylate, 2,4-di(n-propylamido) pyridine,diethyl pyridine-2,5-dicarboxylate, dimethylpyridine-2,5-dicarboxylate,2,4-di(2-hydroxyethylamido)pyridine,2,4-di(3-hydroxypropylamido)pyridine, or mixture thereof.
 33. The regimeor regimen as defined by claim 25, said at least one compound of formula(I) comprising an ester.
 34. The regime or regimen as defined by claim32, comprising administering a thus effective amount of diethylpyridine-2,4-dicarboxylate.
 35. A regime or regimen forinducing/stimulating the growth of human keratinous fibers and/orretarding the loss and/or increasing the density thereof, comprisingadministering to an individual in need of such treatment, a thuseffective amount of at least one compound having the structural formula(I):

in which: R₁ and R₂ are respectively in the 2 and 4 positions of thepyridine ring and wherein R₁ and R₂, which may be identical ordifferent, are each OH, OR¹, wherein R¹ represents a saturated linear orbranched C₁-C₁₀ alky radical.
 36. The regime or regimen of claim 35,wherein R₁ and R₂ are each:


37. The regime or regimen of claim 35, wherein the compound of formula(I) is selected from the group consisting of pyridine-2,4-dicarboxylicacid or its sodium salt, dimethylpyridine-2,4-dicarboxylate, diethylpyridine-2,4-dicarboxylate, diisopropyl pyridine-2,4-dicarboxylate, or amixture thereof.
 38. A regime or regimen for inducing/stimulating thegrowth of human head hair and/or retarding the loss and/or increasingthe density thereof, comprising topically applying onto the hair and/orscalp of an individual in need of such treatment, a thus effectiveamount of at least one compound having the structural formula (I):

in which: R₁ and R₂ are respectively in the 2 and 4 positions of thepyridine ring and wherein R₁ and R₂ which may be identical or different,are each OH, OR¹, wherein R¹ represents a saturated linear or branchedC₁-C₁₀ alky radical.
 39. The regime or regimen of claim 38, wherein R₁and R₂ are each:


40. The regime or regimen of claim 38, wherein the compound of formula(I) is selected from the group consisting of pyridine-2,4-dicarboxylicacid or its sodium salt, dimethylpyridine-2,4-dicarboxylate, diethylpyridine-2,4-dicarboxylate, diisopropyl pyridine-2,4-dicarboxylate, or amixture thereof.
 41. A regime or regimen for treating androgenicalopecia, comprising administering to an individual in need of suchtreatment, a thus effective amount of at least one compound having thestructural formula (I):

in which: R₁ and R₂ are respectively in the 2 and 4 positions of thepyridine ring and wherein R₁ and R₂ which may be identical or different,are each OH, OR¹, wherein R¹ represents a saturated linear or branchedC₁-C₁₀ alky radical.
 42. The regime or regimen of claim 41, wherein R₁and R₂ are each:


43. The regime or regimen of claim 41, wherein the compound of formula(I) is selected from the group consisting of pyridine-2,4-dicarboxylicacid or its sodium salt, dimethylpyridine-2,4-dicarboxylate, diethylpyridine-2,4-dicarboxylate, diisopropyl pyridine-2,4-dicarboxylate, or amixture thereof.